O10.6. OLANZAPINE IMPAIRS CENTRAL INSULIN ACTION: EFFECTS ON BODY FUEL PREFERENCE IN RATS
Notice bibliographique
Résumé
Antipsychotics (APs) remain the cornerstone of treatment in schizophrenia, with increasing use on- and off- label. Olanzapine (OLZ) is a highly prescribed, high metabolic liability AP. Olanzapine has also been found to shift major fuel preference from carbohydrates to fats (while impairing fat breakdown and decreasing availability of fat as a substrate). The shift toward fat utilization is demonstrated by decreases in respiratory exchange ratio (RER). Notably, APs may alter signaling pathways in insulin-sensitive brain areas, particularly in the hypothalamus, that play a role glucose regulation and energy expenditure. We investigated the effects of intracerebroventricular (ICV) insulin administration on OLZ-induced disruptions in energy homeostasis. Male Sprague Dawley rats were assigned to 4 treatment groups (ICV-peripheral): Vehicle (VEH)-VEH (n = 5), Insulin (INS)-VEH (n = 7), INS-OLZ (n = 6), VEH-OLZ (n = 5). Following acclimatization to the metabolic cages, rats received injections of INS (10mU) or VEH into the 3rd ventricle, and OLA (3mg/kg) or VEH subcutaneously at the beginning of the light (7AM, t=0) and dark (7PM, t=12h) cycle. Dose of OLZ was chosen based on clinically relevant >65% dopamine (D2) brain occupancy. Dose of ICV insulin was chosen based on established decreases in food intake. Indirect calorimetry was used to calculate RER, and heat production. Cumulative food intake was measured at 12-hour intervals (t=12h and 24 h). Treatment with OLZ reproduced the previously established downward shift in RER during the dark phase (p=0.016), which occurred independently of changes in food intake or heat production. Central insulin also decreased RER (p=0.013), an unexpected finding as insulin has been associated with increased carbohydrate oxidation. This may have been secondary to decreased food intake associated with central INS (p=0.011), leading to a shift towards fat-oxidation characteristic of fasting. Co-administration of OLZ with central INS (INS-OLZ) abolished the treatment effect seen in the INS-VEH group relative to VEH-OLZ, shifting the RER profile to become similar to the VEH-OLZ group. Similarly, when OLZ was co-administered with ICV-INS, the effect of central INS to reduce food-intake was lost. An interaction effect (p=0.007) was observed between central insulin and subcutaneous OLZ treatments on RER, supporting the notion that these compounds may work through independent mechanisms to influence fuel preference. Taken together, these findings suggest that: 1) central insulin stimulation alters metabolism but is unable to modulate OLZ-specific associated changes in RER; 2) this is likely occurring due to rapid induction of central insulin resistance by OLZ. Our data thus warrants further investigation into the effects of APs on central insulin sensing, and mitigation strategies (i.e. use of central insulin sensitizers) with the goal of mitigating the metabolic burden of these compounds.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,003 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; les deux têtes enseignantes s’accordent sur ce qui est montré ici.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».